Project III: Vitamin D Concentrations, Genetic Modifiers, and Parkinson Disease Parkinson disease (PD) results from genetic and environmental factors and complex interactions between them. Basic science, epidemiology and genetic studies have accumulated evidence supporting a role of vitamin D (vit D) in PD susceptibility. In addition to vit D providing neuroprotection for dopaminergic neurons, low vit D concentrations are more common in and increase risk of PD. Also, vitamin D receptor (VDR) gene polymorphisms appear to modulate risk for and age at onset of PD. However, these VDR polymorphism effects on PD risk vary in different study populations. One explanation is that genetic effects are dependent on 'exposure'to vit D, which varies across populations. For example, in osteoporosis, genetic factors modulate the apparent protective effects of vit D. Because vit D concentration is largely determined by diet and sunlight exposure, vit D blood concentration is modifiable. Vit D supplementation is a potential therapeutic strategy if the link between vit D and PD can be confirmed and better understood. We will jointly analyze the effects of environmental exposure (25-hydroxy-vitamin D (25[OH]D) concentration from blood plasma samples) and the common genetic variants on risk and age at onset of PD. Built on the previous epidemiologic and genetic studies, this study will also provide valuable insights on a gene-environment interaction that may play an important role in PD pathogenesis. Importantly, results of the study will guide future efforts to determine if vit D supplementation can treat or prevent PD, and if people with a certain genetic makeup benefit more from vit D supplementation than others. We hypothesize that plasma vit D concentration modifies the genetic effects of vit D-related genes and that genetic factors modify the effect of vit D on the risk of developing PD. To test our hypothesis, we have developed three specific aims: 1) Evaluate the association of plasma vit D level and risk and age at onset of PD in three case-control samples. 2) Conduct analysis to identify potential vit D-gene interactions underlying PD risk or age at onset. 3) Thoroughly examine vit D-associated genes for functional variants that explain their associations with PD.